ADINA INSTITUTE OF PHARMACEUTICALSCIENCES SAGAR BY ASSO.PROF. IMRAN KHAN

2.  Certain disease and the effect of some drugs
are usually responsible affecting the rhythm
and the normal heart rate. These cardiac
arrhythmia may be caused from disorders in
the normal mechanical activity of the heart
depends upon a specific sequence of electrical
activation for all myocardial cells during each
beat, beginning first at the SA node and ending
with depolarization of the ventricle. Thus
arrhythmia may arise due to alteration in,
Conduction Automaticity Refractory period of
the myocardial cells.


4. 

5.  Class I drugs are generally local anaesthetics acting
on nerve and myocardial membranes to slow
conduction by inhibiting phase 0 of the action
potential. Myocardial membranes show the
greatest sensitivity. Class I drugs decrease the
maximal rate of depolarization without changing
the resting potential. They also increase the
threshold of excitability; increase the effective
refractory period, decrease conduction velocity,
and decrease spontaneous diastolic depolarization
in pacemaker cells. The decrease in diastolic
depolarization tends to suppress ectopic foci
activity. Prolongation of the refractory period
tends to abolish re-entry arrhythmias. This class is
further sub classified into class IA, IB, and IC
based on the primary pharmacologic effect.

6. 

7. 
Quinidine (138) is a d-isomer of quinine. It is obtained from bark of
various species of cinchona and from Remijia pendunculata. Quinidine has a
direct myocardial depressant action. It increases refractory period,
depresses contractility, depresses excitability and slows speed of
conduction in cardiac muscle.

8.  (p-Amino-N-[2diethylamino)-ethyl] benzamide hydrochloride)
(139) differs from local anaesthetic procaine in that the ester
linkage of procaine is replaced by an amide linkage. This
difference had distinct advantages as an antiarrhythmic drug, that
is, greater stability from enzymatic hydrolysis and fewer CNS
effects of procaine. Procainamide is so similar in its action to
quinidine that the two drugs can be used interchangeably. It is
particularly effective in promptly abolishing ventricular
premature depolarization and paroxysmal ventricular
tachycardia. Acute glaucoma and urinary retention is observed.
Procainamide analogs with electron-donating groups (OH, NH2

9.  Disopyramide Phosphate (α-[2-(Di isopro
pylamino) ethyl]-(x-phenyl-2-pyridine
acetamide phosphate) is approved for oral
administration in the treatment of ventricular
arrhythmias as an alternative to quinidine and
procainamide. It has both direct and indirect
actions of the heart, which resemble those of
quinidine. Disopyramide is administered as a
racemic mixture, but its antiarrhythmic activity
resides primarily in the S-enantiomer. It is
metabolised by mono-N-desalkylation with
loss of one Nitroisopropyl group. This
metabolite is responsible for its anticholinergic
actions.

11.  Substitution at the ortho position improved
the biological activity. Ethyl group is optimal.
 Replacement of pyridyl group with acylic
amines gave good compounds. Cyclohexyl
group gave equally potent compound.
Pentenamide showed a longer duration of
action than disopyramide.
 2-Pyridyl is more potent than other isomers.
 Variation in the amino group only di-isopropy
lamine and 2, 6dimethylpiperidine were the
most suitable groups.
 A correlation between n values and ventricular
arrhythmias was obtained

12. 
Lidocaine is similar to procaine, is an effective, clinically used local. Its
cardiac effects, however, are distinctly different from those of
procainamide or quinidine. Lidocaine is normally reserved for the
treatment of ventricular arrhythmias and is, in fact, usually the drug of
choice for emergency treatment of ventricular arrhythmias. Its utility in
these situations is due to the rapid onset of antiarrhythmic effects on
intravenous infusion. In addition, these effects cease soon after the
infusion is terminated. Thus, lidocaine therapy may be rapidly modified
in response to changes in the patient's status. Lidocaine is effective as an
antiarrhythmic only when given parenterally, and the intravenous route
is the most common. Antiarrhythmic activity is not observed after oral
administration because of the rapid and efficient first-pass metabolism
by the liver.

13. 

14. LIDOCANE
Lidocaine is similar to procaine, is an effective, clinically used
local. Its cardiac effects, however, are distinctly different from those
of procainamide or quinidine. Lidocaine is normally reserved for
the treatment of ventricular arrhythmias and is, in fact, usually the
drug of choice for emergency treatment of ventricular arrhythmias

15. 
Phenytoin is most useful in treating ventricular arrhythmias associated
with digitalis toxicity or acute myocardial infarction. CNS side effects are
the most common problems encountered with phenytoin and include
vertigo, loss of mental acuity.

16. FLECAINIDE ACETATE
Flecainide Acetate: (±)-N-(2-piperidinylmethyl)-2, 5bis(2,2,2-
trifluoroethoxy) benzamide (163) represents the first fluorine
containing newer group of antiarrhythmic drugs. It is indicated
for use in patients with life-threatening arrhythmias such as
sustained ventricular tachycardia. It is able at precipitate cardiac
arrest. Other side effects include headache, dizziness and nausea.
The major metabolites, meta-O-dealkyl flecainide and meta-O-
dealkyl flecainide lactam are inactive. The most potent
compounds were having two trifluoroethoxy groups, one of
which was ortho to the carboxamide function.

17. 
Propafenone Hydrochloride: 2'-(2-Hydroxy-3-propyl amino propoxy)-3 -
phenylpropiophenone hydrochloride (169) is useful in supraventricular and
ventricular tachycardias and tachyarrhythmia's. It resembles the β-
adrenoceptor blockers of aryloxypropanolamines. It is administered as a
racemic mixture, wherein the R- enantiomer possesses the antiarrhythmic
activity and the S-enantiomer is a non-selective β-adrenergic antagonist.

18.  PROPRANOLOL
 Propranolol is primarily given orally for long-term
treatment of cardiac arrhythmias. It is useful in
ventricular arrhythmias that are due to enhanced
adrenergic stimulation (from emotional stress,
exercise).

19. Sotalol is effective against both supraventricular and
ventricular arrhythmias. It is a much safer drug than
amiodarone. It has a long half-life (about 15 hours).

20. Amiodarone Hydrochloride: 2-Butyl-3-benzofuranyl)[4-(diethylamino)
ethoxy]-3, 5- diiodophenyl] methenone (173) is an iodinated benzofuran
derivative. Amiodarone suppresses premature ventricular contractions and
ventricular tachycardia. Its use is reserved for the treatment of life
threatening ventricular arrhythmias refractory to other treatment.
Amiodarone is highly lipid-soluble and its half-life is 20-100 days. The
precise mechanism of its action is not known. A depressant effect of the
drug on inactivated sodium channels has been observed. It is also possible
that its antiarrhythmic effects are mediated partly by selectively inhibiting
thyroxine action on the heart.

21.  Class IV antiarrhythmic drugs comprise a
group of agents which selectively block the
slow inward current carried by calcium, i.e.,
calcium channel blockers. The slow inward
current in cardiac cells has been shown to be of
importance for the normal action potential in
pacemaker cells. It has also been suggested that
this inward current is involved in the genesis of
certain types of cardiac arrhythmias.
Administration of a Class IV drug causes a
prolongation of the refractory period in the AV
node and the atria, a decrease in
atrioventricular conduction

22. Verapamil is considered the drug of choice for supraventricular
tachycardia. It is also useful for patients with artrial fibrillation.
Not yet approved, but 60-90 mg of diltiazem can be given every 6
hours for prophylactic control against paroxysmal supraventricular
tachycardia.